This proposal describes an intensive, five year training program designed to allow the principal investigator to successfully bridge the gap between clinical and basic science training, with the ultimate goal of achieving scientific independence in the fields of hematostasis and signal transduction. The candidate is currently a fourth year hematology fellow at the University of Pennsylvania and has spend the last two years in the laboratory of Dr. Charles Abrams, M.D. under the dual guidance of Dr. Abrams and Dr. Lawrence Brass, M.D., Ph.D. During this time, the candidate has intensively pursued laboratory investigation and classroom instruction and is ready for the next phase of training, with progressively independent work and more advanced didactic studies. The environment in which the work will be done is a rich and supportive one, with an abundance of technical and personnel resources available at The University of Pennsylvania, the Hospital of the University of Pennsylvania, and Children's Hospital of Philadelphia. The training program and research are being conducted with the guidance of an advisory committee composed of the candidate's two sponsors and Dr. Joel Bennett, M.D., all of whom are successful clinician-investigators in the Division of Hematology and are aware of the requirements for training young physician-scientists to succeed in independent investigation. The training program and advisory committee will also emphasize the importance of critically reading the scientific literature and hypothesis-generated experimental design. The applicant's research has focused on determining the intracellular localization of pleckstrin, the major substrate for protein kinase C in human platelets. Using a combination of molecular biology and cell biology techniques, the candidate has (1) determined that pleckstrin is both membrane associated and cytoplasmic (2) defined a new role for pleckstrin in modulating cell surface architecture and (3) determined the structural features of the molecule necessary for its morphologic effects and localization. Future experiments described within this proposal focus on (1) defining the functional significance of pleckstrin's intracellular localization and (2) exploring the potential mechanisms by which pleckstrin may change cell morphology. These experiments, in addition to leading to a greater understanding of pleckstrin's role in platelet signaling, will provide the candidate with the opportunity to become adept with a variety of techniques used in cell biology, biochemistry, immunology, and molecular biology. The candidate hopes to use the technical skill, scientific knowledge, and experimental approaches gained during this training period to carry on independent investigations in the area of membrane/cytoskeletal reorganization and its role in hemostasis and thrombosis.